Osmoadaptive GLP-1R signalling in hypothalamic neurones inhibits antidiuretic hormone synthesis and release.
Osmoadaptive GLP-1R signalling in hypothalamic neurones inhibits antidiuretic hormone synthesis and release.
复制标题
DOI：
10.1016/j.molmet.2023.101692
复制
发表时间：
2023-04
影响因子：
8.1
通讯作者：
Murphy, David
中科院分区：
文献类型：
--
作者：
Greenwood, Michael P.;Greenwood, Mingkwan;Barez-Lopez, Soledad;Hawkins, Joe W.;Short, Katherine;Tatovic, Danijela;Murphy, David
抗利尿激素加压素的过度释放与许多疾病有关，包括心血管疾病、糖尿病、肥胖和代谢综合征。曾经被认为是疾病导致的升高，现在的数据支持更重要的致病作用。我们之前已经确定 CREB3L1 是协调下丘脑中加压素合成和释放的转录因子。这里的目标是确定 CREB3L1 协调协调加压素释放的机制。我们挖掘 Creb3l1 敲低 SON RNA-seq 数据来识别下游靶基因。我们继续研究这些基因在下丘脑视上核中响应生理和药理刺激的表达和相关途径。我们使用病毒选择性地敲低视上核中的基因表达并评估生理和代谢参数。我们采用磷酸蛋白质组学策略来研究促进垂体释放激素的机制。我们发现胰高血糖素样肽 1 受体 (Glp1r) 作为下游靶基因，并发现在受刺激的加压素神经元中表达增加。选择性敲低视上核 Glp1rs 导致食物摄入量和体重减少。 GLP-1R 激动剂利拉鲁肽治疗可减少加压素的合成和释放。垂体神经中间叶的定量磷酸蛋白质组学显示，利拉鲁肽启动控制加压素胞吐作用的突触前活性区蛋白的过度磷酸化。总之，我们表明 GLP-1R 信号传导抑制加压素系统。我们的数据表明，水合状态可能会影响 GLP-1R 激动剂的药效学，因此在当前的治疗策略中应予以考虑。鉴定 Creb3l1 作为下丘脑 Glp1r 表达的调节因子。 HNS 的生理刺激会增加 AVP 神经元中 Glp1r 的表达。 SON Glp1rs 的敲低会减少食物摄入、体重和 HNS 流出。 GLP-1R 激动剂利拉鲁肽抑制下丘脑 Avp 合成。垂体的定量磷酸蛋白质组学揭示了可能的机制。
The excessive release of the antidiuretic hormone vasopressin is implicated in many diseases including cardiovascular disease, diabetes, obesity, and metabolic syndrome. Once thought to be elevated as a consequence of diseases, data now supports a more causative role. We have previously identified CREB3L1 as a transcription factor that co-ordinates vasopressin synthesis and release in the hypothalamus. The objective here was to identify mechanisms orchestrated by CREB3L1 that co-ordinate vasopressin release. We mined Creb3l1 knockdown SON RNA-seq data to identify downstream target genes. We proceeded to investigate the expression of these genes and associated pathways in the supraoptic nucleus of the hypothalamus in response to physiological and pharmacological stimulation. We used viruses to selectively knockdown gene expression in the supraoptic nucleus and assessed physiological and metabolic parameters. We adopted a phosphoproteomics strategy to investigate mechanisms that facilitate hormone release by the pituitary gland. We discovered glucagon like peptide 1 receptor (Glp1r) as a downstream target gene and found increased expression in stimulated vasopressin neurones. Selective knockdown of supraoptic nucleus Glp1rs resulted in decreased food intake and body weight. Treatment with GLP-1R agonist liraglutide decreased vasopressin synthesis and release. Quantitative phosphoproteomics of the pituitary neurointermediate lobe revealed that liraglutide initiates hyperphosphorylation of presynapse active zone proteins that control vasopressin exocytosis. In summary, we show that GLP-1R signalling inhibits the vasopressin system. Our data advises that hydration status may influence the pharmacodynamics of GLP-1R agonists so should be considered in current therapeutic strategies. Identification of Creb3l1 as a regulator of Glp1r expression in the hypothalamus. Physiological stimulation of the HNS increases Glp1r expression in AVP neurones. Knockdown of SON Glp1rs decreases food intake, body weight, and HNS outflows. GLP-1R agonist liraglutide inhibits hypothalamic Avp synthesis. Quantitative phosphoproteomics of the pituitary gland reveals possible mechanisms.
登录
查看更多内容
影响因子：
4.2
作者：
Greenwood MP;Greenwood M;Romanova EV;Mecawi AS;Paterson A;Sarenac O;Japundžić-Žigon N;Antunes-Rodrigues J;Paton JFR;Sweedler JV;Murphy D
通讯作者：
Murphy D
影响因子：
2.3
作者：
Sanada, Kenya;Yoshimura, Mitsuhiro;Ikeda, Naofumi;Baba, Kazuhiko;Nishimura, Haruki;Nishimura, Kazuaki;Nonaka, Yuki;Maruyama, Takashi;Miyamoto, Tetsu;Mori, Masatomo;Conway-Campbell, Becky;Lightman, Stafford;Kataoka, Masaharu;Ueta, Yoichi
通讯作者：
Ueta, Yoichi
影响因子：
8.8
作者：
Ding, Cherlyn;Magkos, Faidon
通讯作者：
Magkos, Faidon
影响因子：
2.7
作者：
Balaban, Carey D.;Yates, Bill J.
通讯作者：
Yates, Bill J.
血浆copeptin和糖尿病的风险。
影响因子：
37.8
作者：
Enhörning S;Wang TJ;Nilsson PM;Almgren P;Hedblad B;Berglund G;Struck J;Morgenthaler NG;Bergmann A;Lindholm E;Groop L;Lyssenko V;Orho-Melander M;Newton-Cheh C;Melander O
通讯作者：
Melander O